The preparation of doxycycline and other alpha-6-deoxytetracyclines was first described in Blackwood et al. U.S. Pat. No. 3,200,149 granted Aug. 10, 1965. That patent described their preparation by the catalytic hydrogenation of a corresponding 6-methylene intermediate, e.g., in the case of doxycycline, 11a-chloro-6-deoxy-6-demethyl -6-methylene-5-oxytetracycline, in the presence of a heterogeneous noble metal catalyst, e.g., palladium on carbon. The Blackwood patent disclosed the production, in yields of up to about 50%, of equimolar proportions of the diastereoisomers (epimers) of the 6-deoxytetracyclines. In the case of doxycycline, the patent disclosed the co-production of the corresponding beta epimer, beta-6-deoxy-5-oxytetracycline.
Subsequent efforts have been directed to the development of syntheses for producing the 6-deoxytetracyclines in greater yields and with greater stereoselectivity of formation of the desired alpha epimers, e.g., doxycycline. Thus, Korst U.S. Pat. No. 3,444,198 granted May 13, 1969, disclosed that the stereoselectivity of formation of the alpha epimers may be increased when the noble metal hydrogenation catalyst is poisoned. The Korst patent described the formation of epimeric mixtures of the 6-deoxytetracyclines in total yields of up to about 60%, with the stereoselective production of the alpha epimers in amounts of up to about 90% of the epimeric product mixtures. The use of other noble metal or noble metal salt compositions as heterogeneous hydrogenation catalysts in the production of doxycycline has also been disclosed in the literature. See, for example, Morris U.S. Pat. No. 3,954,862 granted May 4, 1976, and Page U.S. Pat. No. 4,597,904 granted July 1, 1986.
The use of rhodium halide complexes containing tertiary phosphine ligands, e.g., tris(triphenylphosphine)chloro rhodium (I), as homogeneous hydrogenation catalysts was first described by Wilkinson et al. in 1966 (J. Chem. Soc. 1711-32). Subsequently, a number of soluble complexes of platinum metals, particularly rhodium, with halides and tertiary phosphines or the like, have been described as useful in a variety of regiospecific, stereoselective and asymmetric reduction reactions. See Knowles et a)., Chem. Communs. 1445 (1968); Horner et al., Agnew Chem. Int. Ed. 7, 942 (1968); Vol Pin et al., Russian Chemical Reviews, 38, 273-289 (1969); Augustine et al., Ann. N.Y. Sci., 148, 482-91 (1969); Ruesch et al., Tetrahedron, 25, 807-11 (1969); Piers et al., Chem. Communs. 1069-70 (1969); "Aspects of Homogeneous Catalysis", vol. I. pp. 5-75 (1970); Carlo Manfredi, Milan, Italy; "Homogeneous Catalysis, Industrial Applications and Implications", Vol. 70, Advances in Chemistry Series, American Chemical Society; Grubbs et al., J.Am. Chem. Soc., 93, 3062 (1971); Kagan et al, J.Am. Chem. Soc , 94, 6429 (1972); Knowles et al., Chem. Communs. 10 (1972); and Harmon et al., Chem. Rev. 73, 21-52 (1973). Similar disclosures have been made in the patent literature. See, for example, U.S. Pat. Nos. 3,489,786; 3,549,780; and 3,639,439; and British Patent Nos. 1,121,642; 1,121,643; 1,138,601; and 1,219,763.
The use of tris(triphenylphosphine)chloro rhodium(I) and similar rhodium complexes as homogeneous, stereospecific hydrogenation catalysts in the production of doxycycline and other alpha-6-deoxy-5-oxytetracyclines has also been extensively discussed in the patent literature. See, for example, U.S. Pat. Nos. 3,907,890; 3,962,131; 4,001,321; 4,207,258; 4,500,458; 4,550,096; 4,743,699; and French Patent No. 2,216,268.
The present invention is directed to an improved process for the production of doxycycline and other alpha-6-deoxytetracyclines, wherein the desired alpha epimer is produced in both high yield and stereospecificity, employing a hydrogenation catalyst which is substantially cheaper than catalysts heretofore required. Other objects and advantages of the invention will be apparent from the following description of preferred embodiments thereof.